bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023–04–16
eightteen papers selected by
Sergio Marchini, Humanitas Research
  1. Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer.
  2. Liquid Biopsy for Advanced Cancer: An Amplicon-Based Massively Parallel Sequencing Panel Approach to Precision Oncology.
  3. BRCAness, Homologous Recombination Deficiencies, and Synthetic Lethality.
  4. Predictive and robust gene selection for spatial transcriptomics.
  5. Dynamics and specificities of T cells in cancer immunotherapy.
  6. The evolution of lung cancer and impact of subclonal selection in TRACERx.
  7. The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond.
  8. The magic of unraveling genome architecture and function.
  9. Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
  10. Insights into the metastatic cascade through research autopsies.
  11. Spatially Resolved Transcriptomics Deconvolutes Prognostic Histological Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases.
  12. Genomic-transcriptomic evolution in lung cancer and metastasis.
  13. Extrachromosomal DNA appears before cancer forms.
  14. Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos.
  15. The evolution of non-small cell lung cancer metastases in TRACERx.
  16. FISHFactor: A Probabilistic Factor Model for Spatial Transcriptomics Data with Subcellular Resolution.
  17. Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.
  18. A DNA copy number alteration classifier as a prognostic tool for prostate cancer patients.
  1. Front Pharmacol. 2023 ;14 1131342
    Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer.
    Xu Huang, Xiao-Yu Li, Wu-Lin Shan, Yao Chen, Qi Zhu, Bai-Rong Xia.
      Currently, for ovarian cancer, which has the highest mortality rate among all gynecological cancers, the standard treatment protocol is initial tumor cytoreductive surgery followed by platinum-based combination chemotherapy. Although the survival rate after standard treatment has improved, the therapeutic effect of traditional chemotherapy is very limited due to problems such as resistance to platinum-based drugs and recurrence. With the advent of the precision medicine era, molecular targeted therapy has gradually entered clinicians' view, and individualized precision therapy has been realized, surpassing the limitations of traditional therapy. The detection of genetic mutations affecting treatment, especially breast cancer susceptibility gene (BRCA) mutations and mutations of other homologous recombination repair defect (HRD) genes, can guide the targeted drug treatment of patients, effectively improve the treatment effect and achieve a better patient prognosis. This article reviews different sites and pathways of targeted therapy, including angiogenesis, cell cycle and DNA repair, and immune and metabolic pathways, and the latest research progress from preclinical and clinical trials related to ovarian cancer therapy.
    Keywords:  angiogenesis inhibitor; clinical trials; epithelial ovarian cancer; immunotherapy; poly (ADP ribose) polymerase inhibitor; targeted therapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1131342
  2. Methods Mol Biol. 2023 ;2621 111-126
    Liquid Biopsy for Advanced Cancer: An Amplicon-Based Massively Parallel Sequencing Panel Approach to Precision Oncology.
    Kristen Maurer, Cynthia A Schandl.
      Although discovered in the 1940s (Mandel and Metais, C R Seances Soc Biol Fil 142:241-243, 1948), cell-free DNA has only recently become a tool practical for use in clinical settings. The challenges associated with detection of circulating tumor DNA (ctDNA) in patient plasma are many and exist in the pre-analytical, analytical, and post-analytical periods. Initiation of a ctDNA program in a small academic clinical laboratory setting can be challenging. Thus, cost-effective, fast methods should be leveraged to promote a self-supporting system. Any assay should be based on clinical utility and have the potential to adapt in order to maintain relevance in a rapidly developing genomic landscape. Herein is described one of many approaches to ctDNA mutation testing - a massively parallel sequencing (MPS) method that is widely applicable and relatively easy to perform. Sensitivity and specificity are enhanced by unique molecular identification tagging and deep sequencing.
    Keywords:  Actionable mutations; Amplicon; Liquid biopsy; MPS; NGS; Solid tumor panel; ccfDNA; cfDNA; ctDNA
    DOI:  https://doi.org/10.1007/978-1-0716-2950-5_8
  3. Cancer Res. 2023 Apr 14. 83(8): 1173-1174
    BRCAness, Homologous Recombination Deficiencies, and Synthetic Lethality.
    Junko Murai, Yves Pommier.
      The concept of "BRCAness" was first described in 2004 to define the situation in which a homologous recombination repair (HRR) defect in a tumor relates to and phenocopies BRCA1 or BRCA2 loss-of-function mutations. Soon after the discovery of synthetic lethality of PARP1/2 inhibitors in BRCA1- or BRCA2-deficient cells, McCabe and colleagues extended the concept of BRCAness to homologous recombination deficiency (HRD) by studying the sensitivity of cancer cells to PARP inhibitors. They genetically revealed that deficiency in HR-related genes (RAD51, RAD54, DSS1, and RPA1), DNA damage signaling genes (ATR, ATM, CHK1, CHK2, and NBS1), or Fanconi anemia-related genes (FANCD2, FANCA, and FANCC) conferred sensitivity to PARP inhibitors. Thus, cells acquire BRCAness either by genetic inactivation of the BRCA or HRD genes. Here, we briefly review how genomic profiling can identify BRCAness and deficiencies in HRD genes and the current difficulty to apply BRCAness/HRD in the clinic. We also discuss how BRCAness relates to HRD and the utility of evaluating BRCAness/HRD to select therapies with PARP inhibitors (olaparib, rucaparib, niraparib, talazoparib, pamiparib, fuzuloparib), topoisomerase I (TOP1) inhibitors (irinotecan, topotecan, and tumor-targeted TOP1 inhibitors), and platinum derivatives (cisplatin and carboplatin). See related article by McCabe and colleagues, Cancer Res 2006;66:8109-15.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0628
  4. Nat Commun. 2023 Apr 12. 14(1): 2091
    Predictive and robust gene selection for spatial transcriptomics.
    Ian Covert, Rohan Gala, Tim Wang, Karel Svoboda, Uygar Sümbül, Su-In Lee.
      A prominent trend in single-cell transcriptomics is providing spatial context alongside a characterization of each cell's molecular state. This typically requires targeting an a priori selection of genes, often covering less than 1% of the genome, and a key question is how to optimally determine the small gene panel. We address this challenge by introducing a flexible deep learning framework, PERSIST, to identify informative gene targets for spatial transcriptomics studies by leveraging reference scRNA-seq data. Using datasets spanning different brain regions, species, and scRNA-seq technologies, we show that PERSIST reliably identifies panels that provide more accurate prediction of the genome-wide expression profile, thereby capturing more information with fewer genes. PERSIST can be adapted to specific biological goals, and we demonstrate that PERSIST's binarization of gene expression levels enables models trained on scRNA-seq data to generalize with to spatial transcriptomics data, despite the complex shift between these technologies.
    DOI:  https://doi.org/10.1038/s41467-023-37392-1
  5. Nat Rev Cancer. 2023 Apr 12.
    Dynamics and specificities of T cells in cancer immunotherapy.
    Giacomo Oliveira, Catherine J Wu.
      Recent advances in cancer immunotherapy - ranging from immune-checkpoint blockade therapy to adoptive cellular therapy and vaccines - have revolutionized cancer treatment paradigms, yet the variability in clinical responses to these agents has motivated intense interest in understanding how the T cell landscape evolves with respect to response to immune intervention. Over the past decade, the advent of multidimensional single-cell technologies has provided the unprecedented ability to dissect the constellation of cell states of lymphocytes within a tumour microenvironment. In particular, the rapidly expanding capacity to definitively link intratumoural phenotypes with the antigen specificity of T cells provided by T cell receptors (TCRs) has now made it possible to focus on investigating the properties of T cells with tumour-specific reactivity. Moreover, the assessment of TCR clonality has enabled a molecular approach to track the trajectories, clonal dynamics and phenotypic changes of antitumour T cells over the course of immunotherapeutic intervention. Here, we review the current knowledge on the cellular states and antigen specificities of antitumour T cells and examine how fine characterization of T cell dynamics in patients has provided meaningful insights into the mechanisms underlying effective cancer immunotherapy. We highlight those T cell subsets associated with productive T cell responses and discuss how diverse immunotherapies might leverage the pre-existing tumour-reactive T cell pool or instruct de novo generation of antitumour specificities. Future studies aimed at elucidating the factors associated with the elicitation of productive antitumour T cell immunity are anticipated to instruct the design of more efficacious treatment strategies.
    DOI:  https://doi.org/10.1038/s41568-023-00560-y
  6. Nature. 2023 Apr 12.
    The evolution of lung cancer and impact of subclonal selection in TRACERx.
    TRACERx Consortium
      Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.
    DOI:  https://doi.org/10.1038/s41586-023-05783-5
  7. Int J Mol Sci. 2023 Apr 06. pii: 6852. [Epub ahead of print]24(7):
    The Cellular Response to DNA Damage: From DNA Repair to Polyploidy and Beyond.
    Razmik Mirzayans.
      A major challenge in treating patients with solid tumors is posed by intratumor heterogeneity, with different sub-populations of cancer cells within the same tumor exhibiting therapy resistance through different biological processes [...].
    DOI:  https://doi.org/10.3390/ijms24076852
  8. Cell Rep. 2023 Apr 08. pii: S2211-1247(23)00372-8. [Epub ahead of print] 112361
    The magic of unraveling genome architecture and function.
    Maria Pia Cosma, Maria Victoria Neguembor.
      Over the last decades, technological breakthroughs in super-resolution microscopy have allowed us to reach molecular resolution and design experiments of unprecedented complexity. Investigating how chromatin is folded in 3D, from the nucleosome level up to the entire genome, is becoming possible by "magic" (imaging genomic), i.e., the combination of imaging and genomic approaches. This offers endless opportunities to delve into the relationship between genome structure and function. Here, we review recently achieved objectives and the conceptual and technical challenges the field of genome architecture is currently undertaking. We discuss what we have learned so far and where we are heading. We elucidate how the different super-resolution microscopy approaches and, more specifically, live-cell imaging have contributed to the understanding of genome folding. Moreover, we discuss how future technical developments could address remaining open questions.
    Keywords:  3D genome folding; CP: Molecular biology; chromatin conformation; genome organization; live imaging; super-resolution imaging
    DOI:  https://doi.org/10.1016/j.celrep.2023.112361
  9. Nat Med. 2023 Apr 12.
    Evolutionary characterization of lung adenocarcinoma morphology in TRACERx.
    TRACERx Consortium
      Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regions and 121 paired metastatic samples across 248 LUADs from the TRACERx 421 cohort, together with RNA-sequencing data from 463 primary tumor regions, were integrated with detailed whole-tumor and regional histopathological analysis. Tumors with predominantly high-grade patterns showed increased chromosomal complexity, with higher burden of loss of heterozygosity and subclonal somatic copy number alterations. Individual regions in predominantly high-grade pattern tumors exhibited higher proliferation and lower clonal diversity, potentially reflecting large recent subclonal expansions. Co-occurrence of truncal loss of chromosomes 3p and 3q was enriched in predominantly low-/mid-grade tumors, while purely undifferentiated solid-pattern tumors had a higher frequency of truncal arm or focal 3q gains and SMARCA4 gene alterations compared with mixed-pattern tumors with a solid component, suggesting distinct evolutionary trajectories. Clonal evolution analysis revealed that tumors tend to evolve toward higher-grade patterns. The presence of micropapillary pattern and 'tumor spread through air spaces' were associated with intrathoracic recurrence, in contrast to the presence of solid/cribriform patterns, necrosis and preoperative circulating tumor DNA detection, which were associated with extra-thoracic recurrence. These data provide insights into the relationship between LUAD morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk.
    DOI:  https://doi.org/10.1038/s41591-023-02230-w
  10. Trends Cancer. 2023 Apr 12. pii: S2405-8033(23)00031-6. [Epub ahead of print]
    Insights into the metastatic cascade through research autopsies.
    Sonya Hessey, Petros Fessas, Simone Zaccaria, Mariam Jamal-Hanjani, Charles Swanton.
      Metastasis is a complex process and the leading cause of cancer-related death globally. Recent studies have demonstrated that genomic sequencing data from paired primary and metastatic tumours can be used to trace the evolutionary origins of cells responsible for metastasis. This approach has yielded new insights into the genomic alterations that engender metastatic potential, and the mechanisms by which cancer spreads. Given that the reliability of these approaches is contingent upon how representative the samples are of primary and metastatic tumour heterogeneity, we review insights from studies that have reconstructed the evolution of metastasis within the context of their cohorts and designs. We discuss the role of research autopsies in achieving the comprehensive sampling necessary to advance the current understanding of metastasis.
    Keywords:  genomic sequencing; metastasis; research autopsy; tumour evolution
    DOI:  https://doi.org/10.1016/j.trecan.2023.03.002
  11. Cancer Res. 2023 Apr 14. 83(8): 1329-1344
    Spatially Resolved Transcriptomics Deconvolutes Prognostic Histological Subgroups in Patients with Colorectal Cancer and Synchronous Liver Metastases.
    Colin S Wood, Kathryn A F Pennel, Holly Leslie, Assya Legrini, Andrew J Cameron, Lydia Melissourgou-Syka, Jean A Quinn, Hester C van Wyk, Jennifer Hay, Antonia K Roseweir, Colin Nixon, Campbell S D Roxburgh, Donald C McMillan, Andrew V Biankin, Owen J Sansom, Paul G Horgan, Joanne Edwards, Colin W Steele, Nigel B Jamieson.
      Strong immune responses in primary colorectal cancer correspond with better patient survival following surgery compared with tumors with predominantly stromal microenvironments. However, biomarkers to identify patients with colorectal cancer liver metastases (CRLM) with good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary colorectal cancer and CRLM and to interrogate the underlying functional biology that drives disease progression. Samples from patients undergoing synchronous resection of primary colorectal cancer and CRLM were evaluated in detail through histological assessment, panel genomic and bulk transcriptomic assessment, IHC, and GeoMx spatial transcriptomics (ST) analysis. High immune infiltration of metastases was associated with improved cancer-specific survival. Bulk transcriptomic analysis was confounded by stromal content, but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for type II IFN signaling and MHC-class II antigen presentation. In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T cells and neutrophils with enrichment of Notch and TGFβ signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcomes in patients undergoing synchronous resection of CRLM, suggesting that it has potential as a prognostic biomarker. Furthermore, ST analysis has revealed significant intratumoral and interlesional heterogeneity and identified the underlying transcriptomic programs driving each phenotype.
    SIGNIFICANCE: Spatial transcriptomics uncovers heterogeneity between patients, between matched lesions in the same patient, and within individual lesions and identifies drivers of metastatic progression in colorectal cancer with reactive and suppressed immune microenvironments.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2794
  12. Nature. 2023 Apr 12.
    Genomic-transcriptomic evolution in lung cancer and metastasis.
    TRACERx Consortium
      Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
    DOI:  https://doi.org/10.1038/s41586-023-05706-4
  13. Nature. 2023 Apr 12.
    Extrachromosomal DNA appears before cancer forms.
    David H Wang.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-00982-6
  14. Chromosome Res. 2023 Apr 14. 31(2): 15
    Mechanisms of chromosomal instability (CIN) tolerance in aggressive tumors: surviving the genomic chaos.
    Brittiny Dhital, Veronica Rodriguez-Bravo.
      Chromosomal instability (CIN) is a pervasive feature of human cancers involved in tumor initiation and progression and which is found elevated in metastatic stages. CIN can provide survival and adaptation advantages to human cancers. However, too much of a good thing may come at a high cost for tumor cells as excessive degree of CIN-induced chromosomal aberrations can be detrimental for cancer cell survival and proliferation. Thus, aggressive tumors adapt to cope with ongoing CIN and most likely develop unique susceptibilities that can be their Achilles' heel. Determining the differences between the tumor-promoting and tumor-suppressing effects of CIN at the molecular level has become one of the most exciting and challenging aspects in cancer biology. In this review, we summarized the state of knowledge regarding the mechanisms reported to contribute to the adaptation and perpetuation of aggressive tumor cells carrying CIN. The use of genomics, molecular biology, and imaging techniques is significantly enhancing the understanding of the intricate mechanisms involved in the generation of and adaptation to CIN in experimental models and patients, which were not possible to observe decades ago. The current and future research opportunities provided by these advanced techniques will facilitate the repositioning of CIN exploitation as a feasible therapeutic opportunity and valuable biomarker for several types of human cancers.
    Keywords:  CIN; CIN adaptation; CIN tumors therapeutic vulnerabilities; Cancer; Metastasis; Therapy resistance
    DOI:  https://doi.org/10.1007/s10577-023-09724-w
  15. Nature. 2023 Apr 12.
    The evolution of non-small cell lung cancer metastases in TRACERx.
    TRACERx Consortium
      Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.
    DOI:  https://doi.org/10.1038/s41586-023-05729-x
  16. Bioinformatics. 2023 Apr 11. pii: btad183. [Epub ahead of print]
    FISHFactor: A Probabilistic Factor Model for Spatial Transcriptomics Data with Subcellular Resolution.
    Florin C Walter, Oliver Stegle, Britta Velten.
       MOTIVATION: Factor analysis is a widely used tool for unsupervised dimensionality reduction of high-throughput data sets in molecular biology, with recently proposed extensions designed specifically for spatial transcriptomics data. However, these methods expect (count) matrices as data input and are therefore not directly applicable to single molecule resolution data, which are in the form of coordinate lists annotated with genes and provide insight into subcellular spatial expression patterns. To address this, we here propose FISHFactor, a probabilistic factor model that combines the benefits of spatial, non-negative factor analysis with a Poisson point process likelihood to explicitly model and account for the nature of single molecule resolution data. In addition, FISHFactor shares information across a potentially large number of cells in a common weight matrix, allowing consistent interpretation of factors across cells and yielding improved latent variable estimates.
    RESULTS: We compare FISHFactor to existing methods that rely on aggregating information through spatial binning and cannot combine information from multiple cells, and show that our method leads to more accurate results on simulated data. We show that our method is scalable and can be readily applied to large data sets. Finally, we demonstrate on a real data set that FISHFactor is able to identify major subcellular expression patterns and spatial gene clusters in a data-driven manner.
    AVAILABILITY: The model implementation, data simulation and experiment scripts are available under https://www.github.com/bioFAM/FISHFactor.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    Keywords:  Factor Models; Gaussian Processes; Poisson Point; Spatial Transcriptomics; Subcellular Resolution
    DOI:  https://doi.org/10.1093/bioinformatics/btad183
  17. Nat Commun. 2023 Apr 10. 14(1): 2017
    Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA.
    Mingyun Bae, Gyuhee Kim, Tae-Rim Lee, Jin Mo Ahn, Hyunwook Park, Sook Ryun Park, Ki Byung Song, Eunsung Jun, Dongryul Oh, Jeong-Won Lee, Young Sik Park, Ki-Won Song, Jeong-Sik Byeon, Bo Hyun Kim, Joo Hyuk Sohn, Min Hwan Kim, Gun Min Kim, Eui Kyu Chie, Hyun-Cheol Kang, Sun-Young Kong, Sang Myung Woo, Jeong Eon Lee, Jai Min Ryu, Junnam Lee, Dasom Kim, Chang-Seok Ki, Eun-Hae Cho, Jung Kyoon Choi.
      Multi-cancer early detection remains a key challenge in cell-free DNA (cfDNA)-based liquid biopsy. Here, we perform cfDNA whole-genome sequencing to generate two test datasets covering 2125 patient samples of 9 cancer types and 1241 normal control samples, and also a reference dataset for background variant filtering based on 20,529 low-depth healthy samples. An external cfDNA dataset consisting of 208 cancer and 214 normal control samples is used for additional evaluation. Accuracy for cancer detection and tissue-of-origin localization is achieved using our algorithm, which incorporates cancer type-specific profiles of mutation distribution and chromatin organization in tumor tissues as model references. Our integrative model detects early-stage cancers, including those of pancreatic origin, with high sensitivity that is comparable to that of late-stage detection. Model interpretation reveals the contribution of cancer type-specific genomic and epigenomic features. Our methodologies may lay the groundwork for accurate cfDNA-based cancer diagnosis, especially at early stages.
    DOI:  https://doi.org/10.1038/s41467-023-37768-3
  18. Br J Cancer. 2023 Apr 10.
    A DNA copy number alteration classifier as a prognostic tool for prostate cancer patients.
    Walead Ebrahimizadeh, Karl-Philippe Guérard, Shaghayegh Rouzbeh, Eleonora Scarlata, Fadi Brimo, Palak G Patel, Tamara Jamaspishvili, Lucie Hamel, Armen G Aprikian, Anna Y Lee, David M Berman, John M S Bartlett, Simone Chevalier, Jacques Lapointe.
       BACKGROUND: Distinguishing between true indolent and potentially life-threatening prostate cancer is challenging in tumours displaying clinicopathologic features associated with low or intermediate risk of relapse. Several somatic DNA copy number alterations (CNAs) have been identified as potential prognostic biomarkers, but the standard cytogenetic method to assess them has a limited multiplexing capability.
    METHODS: Multiplex ligation-dependent probe amplification (MLPA) targeting 14 genes was optimised to survey 448 tumours of patients with low or intermediate risk (Grade Group 1-3, Gleason score ≤7) who underwent radical prostatectomy. A 6-gene CNA classifier was developed using random survival forest and Cox proportional hazard modelling to predict biochemical recurrence.
    RESULTS: The classifier score was significantly associated with biochemical recurrence after adjusting for standard clinicopathologic variables and the known prognostic index CAPRA-S score with a hazard ratio of 2.17 and 1.80, respectively (n = 406, P < 0.01). The prognostic value of this classifier was externally validated in published CNA data from three radical prostatectomy cohorts and one radiation therapy pre-treatment biopsy cohort.
    CONCLUSION: The 6-gene CNA classifier generated by a single MLPA assay compatible with the small quantities of DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue specimens has the potential to improve the clinical management of patients with low or intermediate risk disease.
    DOI:  https://doi.org/10.1038/s41416-023-02236-8
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